Low Testosterone Associated With Obesity and the Metabolic Syndrome Contributes to Sexual Dysfunction and Cardiovascular Disease Risk in Men With Type 2 Diabetes

Reviews/Commentaries/ADA Statements

¹Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute, Torrance, California
²London Bridge Hospital, London, U.K.
³Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital, and the Department of Metabolism, University of Sheffield Medical School, Sheffield, U.K.
⁴Geriatric Research, Education and Clinical Center, V.A. Puget Sound Health Care System, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
⁵Department of Urology, Mayo Clinic, Rochester, Minnesota
⁶Departments of Psychiatry, Reproductive Medicine, and Urology, NY Weill Cornell College of Medicine, New York, New York
⁷Department of Urology, Boston University School of Medicine, Boston, Massachusetts
⁸Clinical Andrology/Centre for Reproductive Medicine and Andrology, University Clinics of Muenster, Muenster, Germany
⁹Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, St. Luke’s–Baylor Diabetes Program, Houston, Texas

Diabetes Care 2011 Jul; 34(7): 1669-1675. https://doi.org/10.2337/dc10-2339

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Figure 1
Complex multidirectional interactions between testosterone and obesity, metabolic syndrome, and type 2 diabetes mediated by cytokines and adipokines leading to comorbidities such as ED and increased CVD risk. FFA, free fatty acids; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PAI-1, plasminogen activator inhibitor-1.

Table 1

Low testosterone is associated with increased mortality in older men

Study design	n	Follow-up (years)	Mortality	Hazard ratio (95% CI)	Recent studies
Retrospective	858	8	All-cause	1.88 (1.34–2.63)^*	Shores et al. (42)
Prospective	794	20	All-cause and CVD	1.40 (1.14–1.71)^* 1.38 (1.02–1.85)^*	Laughlin et al. (45)
Prospective	2,314	10	All-cause and CVD	2.29 (1.60–3.26)^*	Khaw et al. (43)
Prospective	1,954	7.2	All-cause and CVD	2.32 (1.38–3.89)^*	Haring et al. (44)
Prospective	930	6.9	All-cause and CVD in men with CVD	2.27 (1.45–3.60)^*	Malkin et al. (46)

↵*On the basis of recent publications in which the number of subject is >500 and age of the subjects is >60 years.

Table 2

Randomized trials of testosterone replacement in hypogonadal men with metabolic syndrome or type 2 diabetes

Study	Kapoor et al. (55)	Heufelder et al. (56)	Kalinchenko et al. (57)	Jones et al.^* (37)
Subjects	Type 2 diabetes	New type 2 diabetes/metabolic syndrome	Type 2 diabetes/metabolic syndrome	Type 2 diabetes/metabolic syndrome
Study design	RCT-c	NRCT	RCT-p	RCT-p
n	24	32	184	220
Duration (months)	3	12	6	6/12^*
Medications for diabetes	Diet, oral, insulin	Naive	Diet, oral	Diet, oral
Baseline serum testosterone (nmol/L)	≤8.6	≤10.5	≤6.7	≤10.2
Testosterone formulation	TES injections (200 mg/2 weeks)	Testosterone gel (50 mg/day)	TU depot injections	Testosterone gel (40–80 mg/day)
Treatment effects (changes)
HOMA-IR	−1.7	−0.9	−1.49	−0.54
Fasting glucose (nmol/L)	−1.6	−0.3 (AS)	↔	−0.42 (AS)
Fasting insulin (mIU/mL)	↔	↓	↔	↓(AS)
HbA_1c	−0.37	−0.80	ND	↔ [−0.45]^†
Total cholesterol (nmol/L)	−0.4	ND	↔	↔ [−0.13]
LDL cholesterol (nmol/L)	↔	ND	↔	↔^‡
HDL cholesterol (nmol/L)	↔	↑^§	↔	−0.049^‡
Triglycerides	↔	↓	↔	↔
Lipoprotein a	ND	ND	ND	↓
BMI	↔	↔	↔	↔
Waist circumference	↓	↓	↓	↔
% Body fat	ND	ND	ND	↔
Blood pressure	↔	↓‖	ND	↔

↔, No significant change; ↑, significant increase; ↓, significant decrease; AS, approaching significance (P = 0.05–0.07); ND, not done; NRCT, randomized open label, not placebo-controlled parallel trial; RCT-c, randomized placebo-controlled crossover; RCT-p, randomized placebo-controlled parallel; TES, mixed testosterone esters; TU, testosterone undecanoate depot injections after the first injection followed by another injection at 6 weeks and then injections every 12 weeks. Testosterone gel was dose-adjusted to give total testosterone level >17 nmol/L.
↵*The study by Jones et al. (TIMES2) had no medication changes in the first 6 months unless overriding clinical needs, but medication changes were allowed in the second 6 months for ethical reasons (intention-to-treat group, modified per protocol group where no changes in medications occurred; data not shown).
↵†Significant difference compared with placebo observed after 9 months, but result may be confounded by allowed medication changes.
↵‡Metabolic syndrome subgroup showed significant changes in total cholesterol (−0.34 mmol/L), LDL cholesterol (−0.21 mmol/L), and HDL cholesterol (−0.058 mmol/L).
↵§No figure quoted.
‖Diastolic blood pressure only.